Application for approval for adults unable to consent to their own treatment to participate in a clinical trial (ADRENAL Trial) [2015] NSWCATGD 23

NSW Civil and Administrative Tribunal New South Wales Medium Neutral Citation: Application for approval for adults unable to consent to their own treatment to participate in a clinical trial (ADRENAL Trial) [2015] NSWCATGD 23 Hearing dates: 2 and 22 May 2015 Date of orders: 19 June 2015 Decision date: 19 June 2015 Jurisdiction: Guardianship Division Before: C Fougere, Principal Member H Creasey, Senior Member (Professional) J Koussa, General Member Community Decision: The ADRENAL Trial does not fall within the definition of clinical trial in section 33(1) of the Guardianship Act 1987 (NSW).

Application dismissed. Catchwords: CLINICAL TRIAL – Randomised blinded placebo controlled trial of hydrocortisone in critically ill patients with septic shock – both arms reflect existing, accepted treatment for septic shock – use of hydrocortisone within its TGA registration – consent under Part 5 of the Guardianship Act Legislation Cited: Therapeutic Goods Act 1989 (Cth) Civil and Administrative Tribunal Act 2013 (NSW) Guardianship Act 1987 (NSW) Cases Cited: Alcan (NT) Alumina Pty Ltd v Commissioner of Territory Revenue [2009] HCA 41 Application for approval for adults unable to consent to their own treatment to participate in a clinical trial (AMOUNT Rehabilitation Trial) [2015] NSWCATGD 1 Application for approval for adults unable to consent to their own treatment to participate in a clinical trial (SPICE III Trial) [2014] NSWCATGD 44 P v NSW Trustee and Guardian [2015] NSWSC 579 Project Blue Sky Inc v Australian Broadcasting Authority [1998] HCA 28 Scott v Commercial Hotel Merbein Pty Ltd [1930] VLR 25 Texts Cited: Macquarie Dictionary (online edition) Oxford English Dictionary (online edition) Pearce DC and Geddes RS, Statutory Interpretation in Australia (2011, 7th ed), [2.26] Category: Principal judgment Parties: Professor Bala Venkatesh Representation: Dr Ashley Tsacalos, Legal Representative File Number(s): 4/2015 Publication restriction: Nil

REASONS FOR DECISION

TRIBUNAL'S FINDING 1. For the reasons that follow, the Tribunal determined that the ADRENAL trial does not fall within the definition of 'clinical trial' in section 33(1) of the Guardianship Act 1987 (NSW) ('Guardianship Act'). 2. The application was dismissed.

INTRODUCTION 1. On 31 March 2015, the NSW Civil and Administrative Tribunal ('NCAT') received an application from Professor Bala Venkatesh in relation to the 'ADRENAL' trial: a 'randomised blinded placebo controlled trial of hydrocortisone in critically ill patients with septic shock' (ADRENAL Clinical Protocol Amendment 3, Version 4.0, 25 September 2012 ('Study Protocol')). 2. The trial gains its name from its longer title - 'ADjunctive coRticosteroid trEatment iN criticAlly ilL patients with septic shock' and is funded by a project grant from the National Health and Medical Research Council ('NHMRC'). 3. The ADRENAL trial received approval in NSW from the Sydney Local Health District Human Ethics Review Committee by letters dated 4 July 2011 and 20 March 2012 in relation to earlier versions of the Study Protocol and 25 September 2012 in relation to the current Study Protocol. 4. Section 45AA of the Guardianship Act 1987 (NSW) provides as follows 45AA Tribunal may approve clinical trials (1) The Tribunal may approve, in accordance with this section, a clinical trial as a trial in which patients to whom this Part applies may participate. 1. Even though the application was made pursuant to section 45AA(1), the applicant's primary submission was that the ADRENAL trial ought not be considered a 'clinical trial' within Part 5 of the Guardianship Act. In the applicant's view, ADRENAL involves the comparison of two widely accepted, standard forms of critical care treatment and, as such, does not involve the testing of new drugs or treatments or the experimental study of new applications. The applicant submitted that this type of study was not intended to be the subject of the clinical trial provisions that were introduced into the Guardianship Act by the Guardianship Amendment Bill 1998. The applicant submitted that this interpretation is consistent with previous decisions of the Tribunal and most in line with the stated objects of Part 5 of the Guardianship Act. 2. The Tribunal was informed that although the trial commenced operation in NSW in 2012, it was suspended in January 2015 following decisions of NCAT in Application for approval for adults unable to consent to their own treatment to participate in a clinical trial (SPICE III Trial) [2014] NSWCATGD 44 ('SPICE III') and Application for approval for adults unable to consent to their own treatment to participate in a clinical trial (AMOUNT Rehabilitation Trial) [2015] NSWCATGD 1 ('AMOUNT'). The purpose of the temporary suspension was to enable the evaluation of these decisions. The applicant advised that after consultation with the RPA Zone Ethics Committee, a decision was made to make the current application to NCAT. 3. A critical issue in this case was therefore the meaning of 'clinical trial' in Part 5 of the Guardianship Act and whether or not the ADRENAL trial met that definition.

PROGRESS OF PROCEEDINGS 1. The Tribunal conducted an interlocutory hearing on 29 April 2015. The hearing of the substantive application took place on 1 and 22 May 2015. 2. Leave was granted pursuant to section 45(3)(a) of the Civil and Administrative Tribunal Act 2013 (NSW) ('CAT Act') for Dr Ashley Tsacalos, an Australian legal practitioner, to represent the applicant. 3. A significant part of the hearing on 1 May 2015 was spent dealing with the applicant's submission that the Tribunal should exercise its discretion pursuant to section 54 of the CAT Act to refer a question of law arising in the proceedings to the Supreme Court for the opinion of the Court. This submission was not pressed by the time of the adjourned hearing on 22 May 2015. The Tribunal did not, therefore, need to make any determination in relation to the referral issue. 4. The Tribunal reserved its decision on 22 May 2015. 5. The usual course following a reserved decision is that the Tribunal's order and the written reasons for that order are issued at the same time. At the conclusion of the hearing on 22 May, the applicant's legal representative indicated that the applicant would be content to be provided with the Tribunal's order, when made, with the written reasons to follow at a later time. 6. The Tribunal issued its order dismissing the application on 19 June 2015. These Reasons for Decision followed at a later date.

CONSENT ISSUES 1. As a preliminary issue, the evidence before the Tribunal indicated that the ADRENAL trial is one in which participants are likely to be incapable of providing informed consent as they are 'often unconscious, sedated, intubated and too ill to understand information relating to clinical trial participation' (Study Protocol, page 22). 2. The Study Protocol outlined the consent hierarchy in the event that informed consent could not be obtained from a patient prior to entry into the trial. 3. This hierarchy required, first, prior informed consent from the person responsible for the patient. 4. However, in circumstances where it was not possible or practicable for the patient or the person responsible to provide consent in a timely manner, the Study Protocol provided that 'delayed consent' may be sought from the patient or person responsible as follows (Study Protocol, page 23): c) Delayed consent from patient or SDM [substitute decision maker] As noted, this trial is studying an approved drug and dose in an accepted patient population. Any potential benefit of the drug may only be realised if administered in a timely fashion. Where it is not possible or practicable for the patient or the SDM to provide consent in a timely manner, subject to approval by the relevant HREC [Human Research Ethics Committee] the patient will be enrolled into the study and as soon as possible and appropriate, the SDM will be informed of the patient's participation in the study. At this stage, the SDM will be asked to provide written consent to continue in the study or will be able to refuse or withdraw consent for the patient to continue at any time. If they choose to withdraw the patient, permission to use the study-related data collected up to that time and for permission to collect and use outcome data will be sought. Patients who recover sufficiently to understand the explanation of the study will be asked to provide verbal or written consent (according to local HREC requirements) to continue with the study procedures as soon as possible or be offered the chance to withdraw. If the patient chooses to withdraw from the study procedures, they will be asked for permission to use their study-related data and for permission to collect and use outcome data. 1. The 'Person Responsible Information Sheet and Consent Form (Continue)' (NSW Master Version 3, 11 November 2011) provided in evidence was consistent with this aspect of the Study Protocol in that it invites the person responsible to allow the patient 'to continue to take part in the study' (page 1) and makes explicit (at page 4) that permission was sought from the Human Research Ethics Committee to 'seek permission for your relative/friend's continued enrolment in the study either from you or your relative/friend after the study treatment commenced'. 2. The Tribunal in the SPICE III decision noted (at [120]): whilst the notion of 'delayed consent' may exist in other jurisdictions in Australia and is referred to in the National Statement on Ethical Conduct on Human Research (2007) [Chapter 2.3], it does not exist in the Guardianship Act. The National Statement makes express reference to the fact that an opt-out approach or a waiver of consent approach to recruitment must not be prohibited by state, federal or international law [paragraphs 2.3.6 and 2.3.10]. 1. At the conclusion of the first day of hearing on 1 May 2015, the Tribunal made directions for the provision of written submissions addressing a number of matters including the following: * Legal basis of 'delayed consent' and/or 'consent to continue in the study' sought from a person responsible within Part 5 of the Guardianship Act 1987 (NSW), as described at page 23 of ADRENAL Clinical Protocol Amendment 3, Version 4.0, 25 September 2012 and as approved by the Sydney Local Health District Human Ethics Review Committee by letter dated 4 July 2011 (in relation to Protocol Version 1.1, 29 July 2011), 20 March 2012 (in relation to Protocol Version 1, 7 November 2011) and 20 December 2012 (in relation to Protocol Version 4.0, 25 September 2012). * In particular, what is the legal basis for the consent process outlined in the 'Person responsible information sheet and consent form (continue)', NSW Master Version 3, 11 November 2011 as also approved by the Sydney Local Health District Human Ethics Review Committee? * If not a clinical trial within Division 4A of Part 5 of the Guardianship Act 1987 (NSW), on what legal basis is consent obtained in the ADRENAL trial? 1. The applicant's written submissions (at [4.1]) note that the rationale for the incorporation of a delayed or deferred consent protocol was informed by the NHMRC Guidelines and that paragraph 4.4.13 of those Guidelines outlines when a Human Research Ethics Committee may approve clinical research without the prior consent of the patient, person responsible or organisation authorised by law. The applicant maintained that the ADRENAL study satisfies the criteria listed in 4.4.13 and the 'consent to continue in the study' forms are also in line with recommendations in the NHMRC guidelines. 2. However, the written submissions (at [4.2]) go on to state that the applicant accepts that 'there is no legal basis for delayed consent in respect of receiving medical treatment in New South Wales'. 3. The applicant submitted that the trial could proceed at the relevant NSW sites without the prior consent of the patient or person responsible on the basis that the provisions of section 37(1) of the Guardianship Act had application. In oral submissions made on the applicant's behalf, it was put to the Tribunal that this was the case whether or not the Tribunal determined that the ADRENAL trial fell within the definition of 'clinical trial' in Part 5 of the Act. 4. Section 37 (contained within Division 2 of Part 5 of the Guardianship Act) provides as follows: 37 When treatment may be carried out without any such consent (1) Medical or dental treatment may be carried out on a patient to whom this Part applies without consent given in accordance with this Part if the medical practitioner or dentist carrying out or supervising the treatment considers the treatment is necessary, as a matter of urgency: (a) to save the patient's life, or (b) to prevent serious damage to the patient's health, or (c) except in the case of special treatment-to prevent the patient from suffering or continuing to suffer significant pain or distress. (2) Minor treatment may (subject to subsection (3)) also be carried out on a patient to whom this Part applies without any consent given in accordance with this Part if: (a) there is no person responsible for the patient, or (b) there is such a person but that person either cannot be contacted or is unable or unwilling to make a decision concerning a request for that person's consent to the carrying out of the treatment. (3) The medical practitioner or dentist carrying out, or supervising the carrying out of, minor treatment in accordance with subsection (2) is required to certify in writing in the patient's clinical record that: (a) the treatment is necessary and is the form of treatment that will most successfully promote the patient's health and well-being, and (b) the patient does not object to the carrying out of the treatment. 1. Given the dismissal of the application for the reasons that follow, it was unnecessary for the Tribunal to make findings as to the applicability, or not, of section 37 to the clinical trial provisions contained in Division 4A of Part 5 of the Guardianship Act. 2. A practical outcome, however, of the dismissal of the application is that based upon the applicants submissions as to the applicability of section 37(1) of the Guardianship Act, it is possible that patients may be recruited into the ADRENAL trial in NSW without prior consent from the patient or a substitute decision maker if the treating clinician is satisfied that the provisions of section 37(1) are satisfied. In addition, if a view is taken by the treating practitioner that the treatment being administered in the ADRENAL trial falls within the definition of 'minor treatment', then potentially the provisions of section 37(2) and (3) have application. These provisions are less stringent in terms of the level of satisfaction required of the relevant medical practitioner. They allow for the provision of minor treatment without the consent of a person responsible as long as the relevant medical practitioner certifies in writing in the patient's clinical record that the 'treatment is necessary and is the form of treatment that will most successfully promote the patient's health and well-being and the patient does not object to the carrying out of the treatment'. 3. The purposive character of the protective jurisdiction exercised under the Guardianship Act has been described (P v NSW Trustee and Guardian [2015] NSWSC 579, [52]) as being governed by a central informing idea: that the jurisdiction exists for the care of those who are not able to take care of themselves…and that an exercise of the jurisdiction affecting a person in need of protection must be for the benefit, and in the best interests, of that person as an individual, not for the benefit of the state, or others, or for the convenience of carers…Implicit in the focus on a person in need of protection "as an individual" is respect for his or her autonomy. 1. Having regard to the protective nature of this jurisdiction, a question may arise as to whether it was within the contemplation of the legislature that the provisions of section 37 would be relied upon in the context of randomised controlled trials (whether or not the trial is a 'clinical trial' within Part 5). 2. This question is not one that needs to be answered by the Tribunal in this matter. Rather, the application of section 37 is a matter for the practitioner carrying out or supervising the treatment. It may also be a question to be considered by the relevant Human Research Ethics Committee from whom ethical approval for the trial is sought. 3. The Tribunal also notes that it is a matter for the applicant and, presumably, the Sydney Local Health District Human Ethics Review Committee who approved the Study Protocol and Person Responsible consent forms in NSW, as to whether the Study Protocol and the 'Person Responsible Information Sheet and Consent Form (Continue)' (NSW Master Version 3, 11 November 2011) should remain in their current form given the inclusion of 'delayed consent' and consent to 'continue to take part in the study'.

LEGISLATIVE FRAMEWORK 1. The provisions relating to clinical trials are contained within Part 5 of the Guardianship Act. Part 5 applies to patients who are aged 16 years or over and who are incapable of giving consent to the carrying out of medical or dental treatment (Guardianship Act, section 34(1)). 2. For the purposes of Part 5, a person is regarded as being incapable of giving consent to the carrying out of medical or dental treatment if the person: 1. is incapable of understanding the general nature and effect of the proposed treatment, or 2. is incapable of indicating whether or not he or she consents or does not consent to the treatment being carried out (section 33(2)). 1. The objects of Part 5 are contained in section 32: 32 Objects The objects of this Part are: (a) to ensure that people are not deprived of necessary medical or dental treatment merely because they lack the capacity to consent to the carrying out of such treatment, and (b) to ensure that any medical or dental treatment that is carried out on such people is carried out for the purpose of promoting and maintaining their health and well being. 1. Under section 45AA(1) of the Guardianship Act, the Tribunal may approve a clinical trial as a trial in which patients who are unable to give a valid consent to their own treatment may take part. Before doing so, the Tribunal must be satisfied as to the criteria set out in section 45AA(2) of the Guardianship Act. 2. Section 45AA provides as follows: 45AA Tribunal may approve clinical trials (1) The Tribunal may approve, in accordance with this section, a clinical trial as a trial in which patients to whom this Part applies may participate. (2) The Tribunal may give an approval under this section only if it is satisfied that: (a) the drugs or techniques being tested in the clinical trial are intended to cure or alleviate a particular condition from which the patients suffer, and (b) the trial will not involve any known substantial risk to the patients (or, if there are existing treatments for the condition concerned, will not involve material risks greater than the risks associated with those treatments), and (c) the development of the drugs or techniques has reached a stage at which safety and ethical considerations make it appropriate that the drugs or techniques be available to patients who suffer from that condition even if those patients are not able to consent to taking part in the trial, and (d) having regard to the potential benefits (as well as the potential risks) of participation in the trial, it is in the best interests of patients who suffer from that condition that they take part in the trial, and (e) the trial has been approved by a relevant ethics committee and complies with any relevant guidelines issued by the National Health and Medical Research Council. (3) The fact that a clinical trial will or may involve the giving of placebos to some of the participants in the trial does not prevent the Tribunal from being satisfied that it is in the best interests of patients that they take part in the trial. (4) The Tribunal's approval of a clinical trial under this section does not operate as a consent to the participation in the trial of any particular patient to whom this Part applies. The appropriate consent must be obtained under Division 3 or 4 before any medical or dental treatment in the course of the trial is carried out on the patient. (5) In this section: "ethics committee" means: (a) for so long as there is any relevant Institutional Ethics Committee registered by the Australian Health Ethics Committee established under the National Health and Medical Research Council Act 1992 of the Commonwealth--an Institutional Ethics Committee so registered, or (b) in the absence of such a committee, an ethics committee established by: (i) a local health district or a public hospital, or (ii) a university, being an ethics committee concerned, wholly or partly, with medical research, or (iii) the National Health and Medical Research Council. 1. The definitions for a number of key terms referred to in Part 5 are set out in section 33(1). The definitions relevant to the present case are as follows: 'clinical trial' means a trial of drugs or techniques that necessarily involves the carrying out of medical or dental treatment on the participants in the trial. 'medical or dental treatment' or 'treatment' means: (a) medical treatment (including any medical or surgical procedure, operation or examination and any prophylactic, palliative or rehabilitative care) normally carried out by or under the supervision of a medical practitioner, or (b) dental treatment (including any dental procedure, operation or examination) normally carried out by or under the supervision of a dentist, or (c) any other act declared by the regulations to be treatment for the purposes of this Part, (and, in the case of treatment in the course of a clinical trial, is taken to include the giving of placebos to some of the participants in the trial), but does not include: (d) any non-intrusive examination made for diagnostic purposes (including a visual examination of the mouth, throat, nasal cavity, eyes or ears), or (e) first-aid medical or dental treatment, or (f) the administration of a pharmaceutical drug for the purpose, and in accordance with the dosage level, recommended in the manufacturer's instructions (being a drug for which a prescription is not required and which is normally self-administered), or (g) any other kind of treatment that is declared by the regulations not to be treatment for the purposes of this Part. 'major treatment' means treatment (other than special treatment or treatment in the course of a clinical trial) that is declared by the regulations to be major treatment for the purposes of this Part. 'minor treatment' means treatment that is not special treatment, major treatment or treatment in the course of a clinical trial. 'special treatment' means: (a) any treatment that is intended, or is reasonably likely, to have the effect of rendering permanently infertile the person on whom it is carried out, or (b) any new treatment that has not yet gained the support of a substantial number of medical practitioners or dentists specialising in the area of practice concerned, or (c) any other kind of treatment declared by the regulations to be special treatment for the purposes of this Part, but does not include treatment in the course of a clinical trial. 1. The provisions in Part 5 are also subject to the general principles set out in section 4 of the Guardianship Act. 2. Under section 4, it is the duty of everyone exercising functions under the Guardianship Act with respect to persons who have disabilities to observe the following principles: (a) the welfare and interests of such persons should be given paramount consideration, (b) the freedom of decision and freedom of action of such persons should be restricted as little as possible, (c) such persons should be encouraged, as far as possible, to live a normal life in the community, (d) the views of such persons in relation to the exercise of those functions should be taken into consideration, (e) the importance of preserving the family relationships and the cultural and linguistic environments of such persons should be recognised, (f) such persons should be encouraged, as far as possible, to be self-reliant in matters relating to their personal, domestic and financial affairs, (g) such persons should be protected from neglect, abuse and exploitation, (h) the community should be encouraged to apply and promote these principles. 1. It is well established that the Guardianship Act should be construed beneficially having regard to its protective character (P v NSW Trustee and Guardian [2015] NSWSC 579, [56]). This includes Part 5 of the Act; there is nothing in the objects provisions of Part 5 that would suggest that the provisions of section 4 (contained in Division 1 of the Act) are excluded from consideration. The centrality of the principles contained in section 4, and their role in informing consideration of the provisions in Part 5 of the Act, including the clinical trial provisions, is reinforced by Schedule 6, clause 5(1) of the CAT Act which provides that, when exercising a 'Division function', the Tribunal is under a duty to observe the principles set out in section 4 of the Guardianship Act.

EVIDENCE 1. The Tribunal was provided with evidence and submissions in the form of the Study Protocol, the application and supporting letter dated 30 March 2015, written submissions dated 15 May 2015, the completed National Ethics Application Form dated 22 August 2012, correspondence with the Sydney Local Health District Ethics Review Committee, sample participant and person responsible information sheets and consent forms and a powerpoint presentation. 2. Oral evidence was provided by a number of people listed in Appendix A.

Evidence as to current use of hydrocortisone in treatment of septic shock 1. Septic shock is hypotension or tissue hypoperfusion due to infection. It is a major cause of mortality worldwide. The evidence was that in the Australasian population, epidemiological studies and randomised-controlled trials have demonstrated mortality rates of 37% (Study Protocol, page 7). 2. In his oral evidence, Professor Venkatesh described septic shock as the result of a patient's circulation being compromised because of severe infection. These patients have severe inflammation and circulatory failure because of the complex chemicals that are released into the body as part of the inflammatory response. Steroids, such as hydrocortisone, may be of benefit to these patients as they are known to be anti-inflammatory. 3. Patients with septic shock can also develop what is called adrenal insufficiency, that is, insufficient production of the steroids produced by the adrenal gland. The administration of steroids, such as hydrocortisone, may also be helpful for the treatment of these patients. 4. Based on this knowledge, clinicians have used steroids in patients with septic shock over many years. Over the last 30 years alone, approximately 17 randomised trials of adjunctive therapy with corticosteroids have been conducted around the world with no consensus as to the effectiveness of corticosteroid therapy (Study Protocol, page 7). 5. According to the Study Protocol (pages 7-11), evidence from randomised controlled trials in the 1980s indicated that high doses of corticosteroids, although effective in reversing shock, do not reduce mortality in sepsis and that treatment with high dose corticosteroids has been associated with increased mortality from superinfection. 6. However, the Study Protocol notes that reduced mortality has been reported with low dose hydrocortisone (200-300mg/day) and (at pages 8-11) provides detailed information concerning previous studies concerning the role of corticosteroids in the treatment of septic shock. Reference was made, in particular, to two international randomised controlled trials (a French multi-centre study and the 'CORTICUS' study, a European study) that examined the effect of treatment with corticosteroids on mortality of patients with septic shock. Both compared the administration of hydrocortisone at 200mg/day with placebo and, according to the Study Protocol, produced divergent results. 7. In the French study, published in 2002, shock was reversed more rapidly in patients receiving hydrocortisone and although overall landmark mortality was not reduced, the investigators reported improved survival in patients with a reduced response to corticotropin. Despite a number of limitations of the trial (outlined at Study Protocol, page 8), it had a substantial effect upon clinical practice and subsequent meta-analyses, reviews, and guidelines advocated the use of low-dose hydrocortisone in patients with septic shock. 8. The CORTICUS study, published in 2008, examined the efficacy of low dose hydrocortisone (200 mg/day) compared to placebo in 499 patients with septic shock. The study was halted prematurely when lower than expected recruitment resulted in termination of funding and expiry of the study drug supply. As a result, as noted in the Study Protocol (page 9), the trial was significantly underpowered to detect a clinically important treatment effect. The main findings of this trial were, however: 1. The mortality in the steroid group was 34% as opposed to 31% in controls 2. Shock was reversed more rapidly in patients receiving hydrocortisone 3. In contrast to the French study, the corticotropin stimulation test did not identify a subgroup of patients who benefited from hydrocortisone 1. The Study Protocol notes that neither the CORTICUS trial nor the French study had adequate statistical power to demonstrate a clinically significant reduction of mortality. 2. Whilst trends in smaller studies and meta-analyses point to reduced mortality in patients with septic shock treated with corticosteroids, the uncertainty engendered by the French study and the CORTICUS study has, according to the evidence, led to a lack of consensus amongst intensive care specialists as to the role of hydrocortisone in the treatment of patients with septic shock. 3. The Surviving Sepsis Campaign Guidelines of 2008 (a joint collaboration of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine committed to reducing mortality from severe sepsis and septic shock worldwide) provided qualified support of the use of low dose hydrocortisone in septic shock based on the publication of the CORTICUS study. They recommend that '...intravenous hydrocortisone be given only to adult septic shock patients after it has been confirmed that their blood pressure is poorly responsive to fluid and vasopressor therapy.' 4. The Australian and New Zealand Intensive Care Society (ANZICS) published a position statement commenting they were unable to sponsor the guidelines in general as some components did not have clear supportive evidence. With regard to the recommendations on steroid treatment, the statement noted '...the literature does not provide clear guidance, and practice varies widely among Australian and New Zealand intensive care physicians. This practice variation seems likely to continue until more definitive clinical data are published.' (Study Protocol, page 10). 5. In order to document current practice, a survey of Australian and New Zealand Intensive Care Physicians was undertaken between July - October 2009 to determine the extent of the use of corticosteroids in patients with septic shock and to assess the feasibility of conducting a trial in Australian and New Zealand ICUs. One of the main findings of this survey was that there is substantial variation in practice - 72% of responding clinicians treat patients with septic shock with corticosteroids as a matter of routine, 28% do not. 6. The Study Protocol (at page 12) notes that clinicians are left with substantial uncertainty about the beneficial effects of corticosteroid treatment in patients with septic shock. The Protocol states that 'What is clear is that: There is a biological rationale for the use of corticosteroids in patients with septic shock Corticosteroids have been consistently shown to improve the cardiovascular response to vasopressors in patients with septic shock High dose corticosteroids increase mortality in patients with septic shock The effect of low dose corticosteroids in patients with septic shock remains unresolved and uncertainty gives rise to substantial practice variation

Evidence concerning the ADRENAL trial 1. The objective of the ADRENAL trial is to evaluate the impact of hydrocortisone administered intravenously versus placebo on all-cause mortality at 90 days in critically ill patients with septic shock. The hypothesis is that hydrocortisone, compared to placebo, reduces 90-day all-cause mortality in patients admitted to intensive care units with septic shock. 2. According to the Study Protocol (at page 7), the accepted principles of therapy for septic shock include prompt resuscitation and administration of antibiotics, source control, intravenous fluid therapy and organ system support with vasopressor drugs, mechanical ventilation, and renal replacement therapy as required. 3. Prior to enrolment into the trial, patients will have received those aspects of the accepted principles of therapy as considered appropriate by the treating physician. 4. Patients enrolled into the trial will be randomised into one of two treatment arms via a secure interactive web based system. 5. Depending on the arm of the study into which a patient is randomised, they will receive either IV hydrocortisone 200mg/day or placebo (in the form of saline), administered as a continuous infusion for seven days or until death or until discharge from the intensive care unit (whichever is the earliest). 6. Both the hydrocortisone and placebo vials are completely covered in blinding label and labelled with the appropriate medication kit number. Patients, treating clinicians and study personnel are blinded to study treatment allocation. 7. For all patients, data will be collected at baseline and then daily whilst the patient is in the intensive care unit. Patients will be followed up to day 14, regardless of where the patient resides in the hospital, to monitor the development of bacteraemia. Additional follow up will occur at 90 days and at 6 months post randomisation. 8. The inclusion criteria for the trial (set out in the Study Protocol) are as follows: Patients must be aged 18 years or older Documented site of infection, or strong suspicion of infection Two of the four clinical signs of inflammation: Core temperature > 38 C or < 36 C Heart rate > 90 beats per minute Respiratory rate > 20 breaths per minute, or PaCO2 < 32 mmHg, or mechanical ventilation. White cell count > 12 x 109 /L or < 4 X 109/L or > 10% immature neutrophils Being treated with mechanical ventilation at the time of randomisation (includes BiPAP or CPAP) Being treated with continuous vasopressors or inotropes to maintain a systolic blood pressure > 90mmHg, or mean arterial blood pressure > 60mmHg, or a MAP target set by the treating clinician for maintaining perfusion Administration of vasopressors or inotropes for ≥ 4 hours and present at time of randomisation. 1. Patients will not be eligible for inclusion of the study if they meet any of the following criteria: Met all inclusion criteria more than 24 hours ago Clinician expects to prescribe systemic corticosteroids for an indication other than septic shock (not including nebulised or inhaled corticosteroid) Patients treated with etomidate Patients receiving treatment with Amphotericin B for systemic fungal infections at time of randomisation Patients with documented cerebral malaria at the time of randomisation Patients with documented strongyloides infection at the time of randomisation Death is deemed inevitable or imminent during this admission and either the attending physician, patient or surrogate legal decision maker is not committed to active treatment Death from underlying disease is likely within 90 days Patient has been previously enrolled in the ADRENAL study. 1. Professor Venkatesh described the treatment of septic shock as a time critical intervention requiring an acute resuscitation response in the intensive care unit. The inclusion and exclusion criteria make it evident that the time window for inclusion into the trial is at least four hours after commencement of the administration of vasopressors or inotropes (Inclusion Criterion 6). Exclusion criterion 1 provides the outer limit of 24 hours. 2. Professor Myburgh gave evidence that whilst a minority of patients develop septic shock in the intensive care unit and in relation to these patients, it may be possible to seek consent for entry into the trial from the patient's person responsible (presumably because the person responsible is known to ICU staff), the vast majority of patients are initially treated for septic shock in emergency departments and are referred to the intensive care unit for further management. It was described as 'mainly an ICU disease' but one in which most patients with the disease will first be treated in an emergency department. 3. In relation to the inclusion criterion requiring the administration of vasopressors or inotropes for at least 4 hours (Inclusion Criterion 6), Professor Myburgh noted that the 'time zero' for the trial is the point at which a patient is eligible to begin treatment with vasopressors or inotropes. The commencement of these treatments may occur outside of the intensive care unit (for example, in the emergency department) so the period of time that the intensive care physician has to consider the patient's entry into the trial may well be less than four hours. If in fact a patient has been receiving inotropes, for example, for six hours in the emergency department, the whole four hours during which the patient has been receiving vasopressor or inotrope treatment may have occurred outside the ICU. 4. In reference to the four to 24 hour period for entry into the trial, Dr Finfer emphasised that septic shock is not a static clinical condition and every patient responds differently to the treatment. If a patient responds well to the administration of vasopressors or inotropes within the four hour minimum period (in inclusion criteria 6), then it would not be standard practice to administer corticosteroids to such a patient and that patient would not be eligible for the trial. 5. The upper limit of 24 hours within which a patient can, according to exclusion criterion 1, be entered into the trial was described by Dr Finfer as necessary for reasons of scientific validity. 6. The evidence provided by Professor Myburgh and Dr Finfer also indicated that the use of corticosteroids for the treatment of septic shock, whilst regarded as an accepted treatment in intensive care units, is not considered as such by emergency department physicians. Professor Finfer described emergency department physicians as having 'a different thought process' and they do not treat people with corticosteroids for septic shock. 7. Professor Myburgh attributed this difference in approach as being largely due to 'the behavioural psychology of different parts of medicine'. Within the package of care, the treatment of septic shock is usually commenced in an emergency department and is mostly based on immediate life saving treatments. If a patient with septic shock in the emergency department requires intubation and ventilation and is treated with inotropes and vasopressors, they will end up in an intensive care unit. The evidence was therefore that treatment of septic shock with corticosteroids is seen primarily as an ICU therapy.

Evidence concerning registered use 1. The applicant submitted that the use of hydrocortisone in the ADRENAL trial is in accordance with its licenced use pursuant to the Therapeutic Goods Act 1989 (Cth). 2. In support of this submission, the Tribunal was provided with a copy of the current entry on the Australian Register of Therapeutic Goods for Solu-Cortef Act-O-Vial hydrocortisone (as sodium succinate) 250mg powder for injection and diluent. Noted as one of the specific indications for the use of the drug is 'shock unresponsive to conventional therapy if adrenocortical insufficiency exists or is suspected'. 3. Dr Finfer gave evidence that the rationale for the use of corticosteroids in patients with septic shock who are unresponsive to other forms of treatment, such as vasopressors and the administration of fluids, is that adrenal insufficiency is contributing to the failure of those patients to respond to those other treatments. ICU physicians are therefore using hydrocortisone in these patients to treat adrenal insufficiency, or what is suspected to be adrenal insufficiency. 4. Both Professor Venkatesh and Professor Myburgh agreed with Dr Finfer's evidence about this issue. 5. The Tribunal was also provided with the 'Australian Product Information for Solu-Cortef' as Appendix 1 to the Study Protocol (at page 31). The document is headed 'MIMS Full Prescribing Information'. According to the evidence, this is a document created by Pfizer, the manufacturer of Solu-Cortef (the registered product name for hydrocortisone). 6. Included in the list of conditions for which the use of the drug is indicated, the document states under the heading 'Endocrine Disorders' the following (Study Protocol, page 31): 'Shock unresponsive to conventional therapy if adrenal insufficiency exists or is suspected.' 7. Under the heading 'Warnings', reference is made to a different corticosteroid, solu-medrol, and the following is stated (Study Protocol page 32): Controlled clinical trials have failed to establish the efficacy of Solu-Medrol (methylprednisolone sodium succinate) in the treatment of sepsis syndrome and septic shock. Two studies suggest that treatment of these conditions with Solu-Medrol may increase the risk of mortality in certain patients (ie patients with elevated serum creatinine levels or patients who develop secondary infections after receiving Solu-Medrol). Although this trial used Solu-Medrol only, the manufacturer recommends that Solu-Cortef not be used for septic shock or for sepsis syndrome. (emphasis added) 1. In relation to the information provided in the Product Information, Professor Finfer noted that the manufacturer's recommendation is based on trials involving solu-medrol which is a different corticosteroid. 2. Professor Myburgh gave evidence that the recommendation by the manufacturer was made on the basis of earlier trials involving higher dosages of corticosteroids in which there were some adverse outcomes. This is not the case in the ADRENAL trial in which the uses a dose of 200mg/day which is consistent with other, more recent trials (CORTICUS and the French study noted earlier). 3. The applicant's legal representative submitted that the Product Information reflects the information that the manufacturer provided to MIMS and does not reflect what is contained in the TGA licence. It was submitted that the study drug in the ADRENAL trial is being used in accordance with its TGA licence conditions and not beyond.

APPLICANT'S SUBMISSIONS IN RELATION TO DEFINITION OF CLINICAL TRIAL 1. The applicant made oral and written submissions in relation to the definition of 'clinical trial'. These may be summarised as follows: * The two forms of treatment being compared in the ADRENAL study are the standard principles of treatment without the administration of hydrocortisone (referred to in the study protocol as the 'placebo'), and the standard principles of treatment with the administration of hydrocortisone. * Both treatments involve the infusion of small volumes of fluid (either containing hydrocortisone or saline) into a patient's pre-existing intravenous fluid catheter. * Hydrocortisone is a form of steroid. The use of steroids in the treatment of septic shock is viewed by many clinicians as standard treatment, though there is still no clear consensus as to whether it is beneficial. The ADRENAL Study seeks to provide a definitive answer to this question. * It is critical to considering the issue before the Tribunal to understand that administering hydrocortisone or not administering hydrocortisone results in known and potentially unknown differences in treatment. As such, the study is a comparison of two standard, but different, 'packages of care' that are used in everyday practice in Intensive Care Units in NSW. * Package including hydrocortisone: administering hydrocortisone to patients with septic shock results in a reduction in the doses of vasopressors required to support the failing circulation in a substantive proportion of patients. However, there is uncertainty whether this effect increases the number of patients who survive their acute illness. It is possible that this effect is either unimportant or countered or exceeded by undesirable effects of administering hydrocortisone, such as adverse effects on patient immunity or muscle function. These effects are difficult for treating clinicians to detect in routine practice and may only be quantifiable in the context of a high-quality, randomised controlled clinical study. * Package without hydrocortisone: in the absence of supplemental hydrocortisone, patients with septic shock are likely to require higher doses of vasopressor agents for a longer duration. Similarly, there is uncertainty whether this effect increases the risk of death or other adverse outcomes. Withholding hydrocortisone may also result in beneficial effects that are difficult for treating clinicians to detect in routine practice. Possibilities for the latter include a better immune function and beneficial effects on muscle metabolism or strength. For the purposes of a comparative effectiveness study, this package is defined as a 'placebo', although this may be misleading given that this package constitutes standard care that is currently administered to a substantial proportion of patients in NSW who have septic shock. * Whilst the ADRENAL study focusses on placebo versus corticosteroids, it must be understood and remembered that these are elements in a more extensive regimen designed to reduce the risk of septic shock in this category of critically ill patients. It is to be noted that on average about one in three of these patients will not survive to leave hospital alive. * Although treatment with corticosteroids has long been considered to be beneficial for patients with septic shock, there is substantial uncertainty amongst clinicians about the advantage of its use and clinical practice varies. International surveys and trials indicate that steroids for septic shock are prescribed variably for between 20 - 50% of patients. Accordingly, both forms of treatment being compared in the ADRENAL study are accepted as standard practice, due to clinicians' uncertainty about the role of steroids in the treatment of septic shock. It is not usual practice for patient or third party consent to be sought prior to administering steroids in this setting and whether or not a patient's treatment for septic shock does or does not include the administration of corticosteroids will depend on which clinician is treating them in which hospital and accordingly viewed from the perspective of a patient the actual treatment they receive is determined largely by the play of chance. * Similarly, both the standard, no-steroid treatment and the standard, steroid inclusive treatment are accepted by clinicians as urgent, necessary treatment to save the life of patients who present with septic shock. In particular, it is important to note that it is accepted that any potential benefits of the use of corticosteroids may only be realised if the treatment is administered in a timely fashion. Thus the nature of septic shock and the condition of patients requiring treatment for septic shock means that treatment is exceptionally time critical.

Prior decisions of the Guardianship Tribunal * The Tribunal has an obligation to the applicant and to the other applicants in similar circumstances to apply consistent interpretations to Part 5 of the Act and it is important to have regard to the interpretative approach of the Tribunal following the 1998 Amendment. * The applicant's understanding is that a 'clinical trial' under Part 5 of the Act has previously consistently been interpreted by the Guardianship Tribunal (the predecessor of NCAT) to refer to studies that involve the assessment of new medical treatments or procedures, or the assessment of non- standard treatments or non-standard applications of accepted treatments. Put another way, the hallmark of a 'clinical trial' under the Act was that there was an element of experimentation or trial. However, even this test does not fully embody the relevant factors. * Prior to its decision regarding the SPICE study, the Tribunal had (so far as the Applicant is aware) consistently ruled that studies involving the comparison of different treatments, both or all of which are accepted as part of current standard practice and are available to patients as standard care in an off-study setting, did not constitute 'clinical trials'. In any case, the Applicant submits that the ADRENAL Study can be clearly distinguished from the SPICE study quite simply on the basis that the latter involved the use of a treatment outside its registered use.

Randomisation * A virtually invariable characteristic of any clinical study involving a comparison of two things is the concern about bias. Bias can manifest itself in many ways, but it is typically sought to be addressed in these sorts of studies by using randomisation, and blinding. Typically the blinding used is 'double blinding', that is neither the doctor nor patient know what drug or procedure is being administered to the patient. * The Applicant acknowledges that, although the ADRENAL study involves two methods of standard treatment, it does involve randomisation. NCAT's recent decision in the AMOUNT trial appeared to indicate that a study involving randomisation will necessarily mean that the study is a 'clinical trial'. While the Applicant disputes that this interpretation is correct based on a reading of the Act, it is not, in any event, applicable to the ADRENAL Study. The ADRENAL Study's exclusion criteria are designed to eliminate all patients with indications which may guide a clinician to either administer or withhold corticosteroids. In other words, by the time a patient is eligible to be enrolled in the study, both methods of treatment are considered equally appropriate for that patient. The 'randomisation' aspect of the study, therefore, is not 'experimental' but rather 'comparative', and should not be considered indicative of a 'clinical trial'. * Viewed from the patients' perspective, there is no certainty at all as to what treatment they might receive, this will depend on a multitude of essentially random factors, such as which hospital they go to, what ICU protocols that hospital might have, and which doctor happens to be there at the time, and his or her experience.

FINDINGS IN RELATION TO THE EVIDENCE 1. Having regard to the written evidence provided in this matter, the expertise of the applicant and other witnesses giving evidence in relation to this application, and noting the absence of a contradictor, the Tribunal accepted that the following matters were established to the requisite civil standard. 2. There are accepted principles of therapy for the treatment of septic shock whether the patient receives this treatment in an Australian emergency department or an intensive care unit. These include prompt resuscitation and administration of antibiotics, source control, intravenous fluid therapy and organ system support with vasopressor drugs, mechanical ventilation, and renal replacement therapy as required 3. The administration of a low dose of hydrocortisone, described as 200-300 mg/day, is also a drug administered by many intensive care unit clinicians, but not emergency department clinicians. 4. Corticosteroids have been utilised for many years to treat septic shock and continues to be administered by many Australian ICU clinicians. There is, however, substantial variation in practice. The results of a 2009 survey of Australian and New Zealand Intensive Care Physicians (referred to earlier) indicated that 72% of responding clinicians treat patients with septic shock with corticosteroids as a matter of routine and 28% do not. The applicant submitted that international surveys and trials indicate that steroids for septic shock are prescribed variably for between 20-50% of patients. 5. The use of low dose hydrocortisone in the treatment of septic shock therefore varies amongst intensive care unit clinicians. Patients with septic shock who are being treated in an intensive care unit may or may not be administered low dose hydrocortisone depending on the preference and experience of the individual clinician treating them. This can vary between hospitals and between clinicians within the same hospital. 6. Despite a number of Australian and international trials over a number of years, there is no scientific consensus as to whether the use of low dose hydrocortisone for the treatment of septic shock is beneficial, harmful or has a neutral effect. 7. The ADRENAL trial is a randomised blinded placebo controlled trial of low dose hydrocortisone in critically ill patients with septic shock. 8. All patients who are potentially eligible for recruitment into the trial will be treated in accordance with the accepted principles of therapy for septic shock. 9. Patients who meet the inclusion criteria and are not excluded as a result of meeting the exclusion criteria will then, depending on the arm of the study into which they are randomised, receive either IV hydrocortisone 200mg/day or a placebo (saline solution). 10. Based on the evidence presented, the Tribunal was satisfied that the hydrocortisone arm of the ADRENAL trial, administered in accordance with the Study Protocol, reflects an existing, accepted treatment for septic shock. 11. Patients entered into the placebo arm of the ADRENAL will not receive hydrocortisone but will receive saline as a placebo in order to blind the study. They will, however, receive treatment in accordance with the accepted principles of therapy for the treatment of septic shock. To this extent, the Tribunal was satisfied that the placebo arm of the trial, administered in accordance with the Study Protocol, reflects accepted treatment for septic shock namely treatment in accordance with the accepted principles of therapy for the treatment of septic shock without the administration of hydrocortisone. 12. The use of IV hydrocortisone 200mg/day in the hydrocortisone arm of the ADRENAL trial is in accordance with its registered use in the Australian Register of Therapeutic Goods. The Tribunal accepted the evidence of Professors Finfer, Venkatesh and Myburgh that hydrocortisone used in the treatment of septic shock in circumstances where a patient is unresponsive to other forms of treatment (such as vasopressors and inotropes), is treatment for, or what may be suspected to be, adrenal insufficiency. This use is consistent with the ARTG entry (167894) for 'Solu-Cortef Act-O-Vial hydrocortisone (as sodium succinate) 250mg powder for injection and diluent dual chamber vial' in which a specific indication (as at 15/12/2004) is 'shock unresponsive to conventional therapy if adrenocortical insufficiency exists or is suspected'. 13. The Tribunal noted the evidence concerning the recommendation made by the manufacturer in the Product Information document (attached as Appendix 1 to the Study Protocol (at page 31) and referred to in the ARTG entry under the heading 'Warnings') that Controlled clinical trials have failed to establish the efficacy of Solu-Medrol (methylprednisolone sodium succinate) in the treatment of sepsis syndrome and septic shock. Two studies suggest that treatment of these conditions with Solu-Medrol may increase the risk of mortality in certain patients (ie patients with elevated serum creatinine levels or patients who develop secondary infections after receiving Solu-Medrol). Although this trial used Solu-Medrol only, the manufacturer recommends that Solu-Cortef not be used for septic shock or for sepsis syndrome. 1. However, this recommendation did not alter the finding of the Tribunal that the use of hydrocortisone in the ADRENAL trial is in accordance with its registered use in the Australian Register of Therapeutic Goods on the basis that: * as noted by Professor Finfer, the manufacturer's recommendation in the Product Information document is based on a trial/s of a different corticosteroid, namely solu-medrol * the Tribunal placed weight on Professor Myburgh's evidence that the recommendation in the Product Information document is based on earlier trials that used higher dosages of the corticosteroid than is the case in the ADRENAL trial * the recommendation in the Product Information document potentially contradicts the stated indication for the use of the drug in the ARTG entry (and earlier in the Product Information document itself at page 31 of the Study Protocol) which lends further weight to Professor Myburgh's evidence that the manufacturer's recommendation in the Product Information is based on the result of trials involving higher doses of solu-medrol. * The Tribunal placed greater weight on the entry in the ARTG summary as reflecting the approved indication for the study drug in question

TRIBUNAL'S REASONING - MEANING OF 'CLINICAL TRIAL' 1. The applicant's primary argument is that the Tribunal should adopt a construction of the term 'clinical trial' so as to exclude studies of standard treatments. 2. The Guardianship Act defines 'clinical trial' in section 33(1) as 'a trial of drugs or techniques that necessarily involves the carrying out of medical or dental treatment on the participants in the trial'. 3. Medical treatment is defined as treatment 'normally carried out by or under the supervision of a medical practitioner' and includes 'any medical or surgical procedure, operation or examination and any prophylactic, palliative or rehabilitative care'. As previously noted, excluded from the definition are a number of types of treatment. 4. There are no other relevant definitional sections contained in Part 5. 5. The Tribunal in the SPICE III decision (at [85]-[91]) considered the dictionary definition of the word 'trial' in the Macquarie Dictionary (online edition) and the Oxford English Dictionary (online edition) and noted that the ordinary, plain English meaning offered a number of alternatives to the meaning of 'trial' that was not limited to new or experimental treatment. The Tribunal found (at [91]) that SPICE III was 'testing something, or putting something to the proof, namely the hypothesis that Early Goal Directed Sedation, compared to standard care sedation, reduces 90 day all cause mortality in critically ill patients who require mechanical ventilation. Patients are randomised into one of two arms in order to test the hypothesis' and that it was 'artificial to describe this process as anything other than a "trial" as per the ordinary meaning of that term'. 6. The Tribunal concluded, however, (at [92]) that it was not necessary to undertake a detailed examination of the context and legislative purpose of the clinical trial provisions in Part 5 to determine whether the meaning of 'trial' should be limited in the manner suggested by the applicant in that case and as referred to in earlier Tribunal decisions. This was because the Tribunal was satisfied that 'even if, for the sake of argument, the meaning of "clinical trial" was to be limited in the manner suggested by the applicant, SPICE III satisfies this narrower view of the term on the basis that the trial proposes the use of dexmedetomidine beyond its TGA registration.' 7. The Tribunal further noted (at [99]) that this finding was 'consistent with the objects of Part 5 of the Guardianship Act, the general principles set out in section 4 of the Act and the additional level of scrutiny that the clinical trial provisions of the Act provide when approval is sought for the participation of people in a trial who lack the capacity to provide their own consent to do so.' 8. As ADRENAL is not a trial involving a drug to be administered beyond its TGA registration, that aspect of the Tribunal's reasoning in SPICE III may be distinguished and it is therefore appropriate to undertake an examination of the context and legislative purpose of the clinical trial provisions. This necessitates an examination of the term 'clinical trial' within the context of Part 5 and the Guardianship Act as a whole.

General principles 1. As was noted by the Tribunal in the SPICE III decision (at [86]), the task of statutory interpretation 'must begin with a consideration of the text itself' (Alcan (NT) Alumina Pty Ltd v Commissioner of Territory Revenue [2009] HCA 41 ('Alcan'), [47] (Hayne, Heydon, Crennan, Kiefel JJ). A majority of the High Court in that case noted (at [47]) that Historical considerations and extrinsic materials cannot be relied on to displace the clear meaning of the text. The language which has actually been employed in the text of the legislation is the surest guide to legislative intention. The meaning of the text may require consideration of the context, which includes the general purpose and policy of a provision, in particular the mischief it is seeking to remedy. (footnotes omitted) 1. The context and purpose of a provision are important to its proper construction because, as was noted in Project Blue Sky Inc v Australian Broadcasting Authority [1998] HCA 28, [69] (McHugh, Gummow, Kirby, Hayne JJ): [t]he primary object of statutory construction is to construe the relevant provision so that it is consistent with the language and purpose of all the provisions of the statute. The meaning of the provision must be determined "by reference to the language of the instrument viewed as a whole". In Commissioner for Railways (NSW) v Agalianos, Dixon CJ pointed out that "the context, the general purpose and policy of a provision and its consistency and fairness are surer guides to its meaning than the logic with which it is constructed". Thus, the process of construction must always begin by examining the context of the provision that is being construed. (footnotes and citations omitted)

The text 1. The breadth of the definition of 'clinical trial' in section 33(1) was noted by the Tribunal in the AMOUNT decision (at [34]): …the definition of clinical trial is very broad. It covers any medical or dental treatment and is not confined to experimental or intrusive procedures. The definition of treatment specifically excludes identified procedures such as non-intrusive examination for diagnosis purposes and first-aid medical and dental treatment. Relevantly, section 33(1)(g) provides for the regulations to exclude certain treatment from the clinical trial regime. It is therefore clear that Division 4A is intended to operate broadly. If the legislature had intended to confine the clinical trial regime it could have easily done so by excluding research or non-intrusive procedures from the definition of treatment. Similarly, such procedures could be excluded by regulation. There is no such exclusion in the Guardianship Regulation 2010 (NSW). The language used in Part 5 is unambiguously wide. Accordingly, there is no need or justification for reading down the provisions or seeking guidance from extrinsic sources (Alcan). 1. The definition of 'special treatment' in section 33(1) also arguably provides support for the view expressed by the Tribunal in AMOUNT. In section 33(1): "special treatment" means: … (b) any new treatment that has not yet gained the support of a substantial number of medical practitioners or dentists specialising in the area of practice concerned, or … but does not include treatment in the course of a clinical trial. 1. The legislation makes explicit reference to 'new treatment' in the relevant part of the definition of 'special treatment'. It is arguable that if the legislature had intended that the clinical trial provisions in Division 4A have application only to drugs or techniques that are new treatments, then it could have made this explicit and adopted the same or similar wording as the definition of 'special treatment' and made reference to 'new treatment'. 2. The applicant submitted that limited weight, if any, should be placed on the use of the words 'new treatment' in the definition of 'special treatment'; that the clinical trial provisions introduced in 1998 Act were 'classic bolt on' provisions without, it seems, a great deal of thought being given to consequences; and that the definition of 'special treatment in sub-section (b) should not be used as a basis to infer what falls within the definition of 'clinical trial'. 3. In the Tribunal's view, the import of the language in the definition of 'special treatment' is not to be lightly discarded given that the employment of different language in the same Act may show that the legislature had in view different objects (Scott v Commercial Hotel Merbein Pty Ltd [1930] VLR 25, [30] (Irvine CJ)). 4. However, attention must also be given to the provisions contained in section 45AA of the Guardianship Act. Under section 45AA(1), the Tribunal may approve a clinical trial, but only if the satisfied of the matters set out in section 45AA(2). 5. Read as a whole, the sub-sections of section 45AA(2), each of which must be satisfied before the Tribunal may consider exercising its discretion to approve a clinical trial, lend weight to the view that 'clinical trial' in Part 5 has a more limited meaning than the broad definition of the term in section 33(1) might otherwise suggest. 6. This view may be inferred from the reference in section 45AA(2)(c) to the 'development of drugs or techniques' having 'reached a stage at which safety and ethical considerations makes it appropriate that the drugs or techniques be available to patients who suffer from that condition…'. 7. As a general principle, all words in a statute must prima facie be given some meaning and effect (Pearce DC and Geddes RS, Statutory Interpretation in Australia (2011, 7th ed), [2.26]). It is difficult to see what meaning or effect the sub-section would have unless it is directed to drugs or techniques that are not currently accepted forms of treatment for the condition in question. This is because drugs or techniques that are accepted forms of treatment for the condition would already be available to patients who suffer from that condition. 8. Two other sub-sections of section 45AA(2) also lend weight to this construction of 'clinical trial'. 9. Section 45AA(2)(b) requires the Tribunal, when there are 'existing treatments for the condition concerned', to be satisfied that the trial will not involve 'material risks greater than the risks associated with those [existing] treatments'. This sub-section may suggest that what is being tested in a trial is a new treatment that is to be compared, in terms of material risk, against the accepted, existing treatments for the condition in question. 10. Section 45AA(2)(d) requires that the Tribunal be satisfied that 'having regard to the potential benefits (as well as potential risks) of participating in the trial, it is in the best interests of patients who suffer from that condition that they take part in the trial'. 11. Arguably, this sub-section has meaning and effect if what is offered by way of participation in the trial is access to a new drug or technique for the condition concerned on the basis that the sub-section contemplates that the only way that patients will gain access to the drug or technique is if they take part in the trial.

Legislative purpose 1. Context and legislative purpose will cast light upon the sense in which the words of the statute are to be read, context here used in a wide sense referable, inter alia, to the existing state of the law and the mischief which the statute was intended to remedy (Alcan, [4] (French CJ)). 2. The Second Reading Speeches associated with the Guardianship Amendment Bill indicate that section 45AA and the other clinical trial provisions were introduced primarily as a result of the difficulties posed by clinical trials involving placebos. Prior to the amendments, consent could be sought for treatment that fell within the definition of 'special treatment' in section 33(1)(b) as 'any new treatment that has not yet gained the support of a substantial number of medical practitioners or dentists specialising in the area of practice concerned'. However, an application for such treatment could only be approved by the then Guardianship Tribunal if, amongst other things, it was satisfied that the patient would in fact receive the treatment. The amendments clarified that, in relation to clinical trials in which placebos were included, a person with a decision making disability could still be included in the trial. 3. Relevantly, the Second Reading Speech makes reference to 'new treatments' and 'that people who cannot consent to their own treatment should have access to new treatments provided certain stringent safeguards are met.'

Conclusion 1. A textual reading of the provisions relating to clinical trials in Part 5 of the Guardianship Act has led the Tribunal to the conclusion, on balance, that the definition of 'clinical trial' in section 33(1) of the Act, despite the breadth of the definition in that section and the language used in the definition of 'special medical treatment' in the same definitional section, should be interpreted as excluding trials of a currently accepted treatment for the condition in question. An examination of the provisions in section 45AA(2) supports this narrower view of the definition of 'clinical trial'. As previously outlined, 45AA(2)(c) would appear to only have meaning and effect if what is under consideration is a trial of drugs or techniques that are not accepted forms of treatment for the condition in question. Sub-sections (2)(b) and (2)(d) of section 45AA section 45AA(2) also lend weight to this construction of 'clinical trial'. 2. This understanding of the definition of 'clinical trial' is also consistent with what may be discerned as to the legislative purpose of the provisions relating to clinical trials in Part 5 based on an examination of the relevant extrinsic material. 3. Whether a drug or technique to be tested in a trial is a currently accepted treatment for a condition or whether it is properly regarded as new or experimental treatment will be a matter that needs to be considered on a case-by-case basis as the question of what is an accepted, established treatment may be open to interpretation. This is likely to involve consideration of a number of factors including, as noted in the SPICE III decision, whether or not the treatment in question is being used within its licensed parameters. 4. This approach is consistent with the protective jurisdiction exercised under the Guardianship Act and the paramount consideration that must be given the welfare and interests of people with decision making disabilities. 5. To avoid any potential confusion, the Tribunal regards it as a matter for those proposing to carry out the treatment to consider if the drug or technique is a currently accepted treatment for a condition or if it is properly regarded as new or experimental treatment and whether, as a result, an application should be made pursuant to section 45AA of the Guardianship Act seeking approval for the clinical trial as a trial in which patients to whom Part 5 of the Guardianship Act applies may participate. 6. As noted in these Reasons for Decision, the evidence presented in this matter persuaded the Tribunal to the requisite civil standard that hydrocortisone is not a new or experimental treatment for septic shock. It has been used in the treatment of this condition in intensive care units for many years, albeit that its use varies amongst clinicians and there has been no consensus as to the effectiveness of corticosteroid therapy for the condition. The evidence also persuaded the Tribunal that hydrocortisone is to be used in accordance with its TGA registration in the ADRENAL trial. 7. These findings led the Tribunal to conclude that the ADRENAL trial, as described in the Study Protocol, does not fall within the definition of 'clinical trial' in section 33(1) of the Guardianship Act and the application was dismissed.

APPENDIX A The following people participated in one or both hearing dates on 1 and 22 May 2015: * Professor Bala Venkatesh, applicant and Chief Investigator for the ADRENAL trial, Intensive Care Specialist, Princess Alexandria Hospital * Professor John Myburgh, Director, Critical Care and Trauma, The George Institute for Global Health * Professor Simon Finfer, Professorial Fellow, The George Institute for Global Health * Dr Manoj Saxena, Intensive Care Physician, St George Hospital * Ms Dorrilyn Rajbhandari, ADRENAL Project Manager, The George Institute for Global Health * Professor Robert Loblay, Chair of Sydney Local Health District Human Research and Ethics Committee * Professor David Cook, Deputy Chair of Sydney Local Health District Human Research and Ethics Committee * Dr Roy Donnelly, Legal Director (Health Law and Research), Sydney Local Health District * Ms Ann O'Neill, Associate Director for the Office for Health and Medical Research in NSW Ministry of Health

********** I hereby certify that this is a true and accurate record of the reasons for decision of the Civil and Administrative Tribunal of New South Wales. Registrar DISCLAIMER - Every effort has been made to comply with suppression orders or statutory provisions prohibiting publication that may apply to this judgment or decision. The onus remains on any person using material in the judgment or decision to ensure that the intended use of that material does not breach any such order or provision. Further enquiries may be directed to the Registry of the Court or Tribunal in which it was generated. Decision last updated: 02 October 2015